Abstract Endometriosis remains one of the most enigmatic gynecologic pathologies, the effects of which can be physically and mentally debilitating. Endometriosis is likely dependent not only on circulating steroid hormones but also on aberrant immunologic response. Case-control studies have observed abnormal levels and function of growth factors, macrophages, and pro-inflammatory cytokines in the peritoneal fluid and serum of women with endometriosis. A few studies suggest increased risk of autoimmune diseases among women with endometriosis. Immune dysfunction and inflammation are also associated with increased risk of diabetes mellitus and cardiovascular disease. Recent studies suggest insulin resistance and vascular inflammation among those with endometriosis. Abnormalities in fibrinolysis associated with endometriosis may increase the risk of arterial plaque formation and consequent ischemic cardiovascular disease. Over 2000 laparoscopically-confirmed incident cases of endometriosis have been observed within the Nurses' Health Study II, and over 500 within the Black Women's Health Study ongoing, prospective cohort studies that began when 116,000 women were enrolled in 1989 and 59,000 in 1995, respectively. In the late 1990s, the NHSII collected and stored blood samples from 30,000 participants, of whom more than 200 were subsequently diagnosed with endometriosis. We propose the first prospective study to assess the following hypotheses: Aim 1: Inflammation is associated with endometriosis. Specifically, higher endogenous levels of C-reactive protein, IL-1, IL-6, and sTNFR1 and sTNFR2 soluble receptors increase the risk of endometriosis. Aim 2: Women with endometriosis are at greater risk of autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and Grave's disease. Aim 3: Women with endometriosis exhibit signs of and are at greater risk for chronic diseases associated with inflammation and fibrinolytic pathology. Specifically, a) Higher endogenous levels of c-peptide, insulin, leptin, and lower levels of adiponectin increase the risk of endometriosis. b) Women with endometriosis are at greater risk of hypertension, hypercholesterolemia, type 2 diabetes, myocardial infarction, and ischemic stroke. c) Those with a diet that includes a high glycemic load and of a pattern consistent with a western diet compared to a prudent diet are at greater risk of endometriosis. These data present a unique opportunity for large-scale, prospective study of the risk factors and consequences of endometriosis. Project Narrative: Endometriosis can be physically and mentally debilitating and may be associated with increased risk of autoimmune and cardiovascular disease. We propose to study over 116,000 women in the Nurses' Health Study II and 59,000 women in the Black Women's Health Study both large, prospective cohorts to learn how immunologic and inflammatory milieu relates to endometriosis via biomarker assay and association with subsequent chronic diseases. We believe that quantifying these factors may improve our understanding of the etiology and consequences of endometriosis.